1. Field of the Invention
The present invention relates to novel seleno compounds containing nitrone moiety, their preparation and pharmaceutical compositions containing the novel compounds as active ingredients, more particularly, to novel seleno compounds containing nitrone moiety, a process for the preparation of the same, the use of the novel compounds as therapeutics for treating and/or preventing various medical dysfunctions and diseases caused by reactive oxygen species (ROS), in particular stroke, Parkinson""s disease, and Alzheimer""s disease.
2. Description of the Prior Art
According to Harman""s free-radical theory of ageing, successive oxidation attacks create xe2x80x9coxidative stressxe2x80x9d conditions, that is, create an imbalance between the protective systems in favour of the pro-oxidants.. Such attacks result in numerous molecular modifications, especially of polyunsaturated membrane lipids, proteins and nucleic acids. Human and animal organisms possess various defense mechanisms that act in synergy. Those mechanisms are of an enzymatic nature (superoxide dismutase, catalase, and glutathione peroxidase) or of a non-enzymatic nature (such as vitamins E and C, which enable physiological control of free-radical activity). With ageing, however, that protection becomes less efficient, not to say inefficient, especially as a result of the decreased activity of a large number of enzymes including those involved in such defense mechanisms. Consequently, for some disorders associated with ageing, such as atherosclerosis, cataract, non-insulin-dependent diabetes, cancer or chronic neurodegenerative disorders, numerous studies have been able to demonstrate that such conditions are associated with those xe2x80x9coxidative stressxe2x80x9d conditions.
The central nervous system is especially sensitive to xe2x80x9coxidative stressxe2x80x9d because of its high oxygen consumption, the relatively low levels of its antioxidant defenses and the high iron concentration of some cerebral regions. This explains why xe2x80x9coxidative stressxe2x80x9d might be one of the main etiological factors of cerebral ageing, as well as of acute central nervous system disorder such as stroke, neurodegenerative disorders such as Parkinson""s disease, Alzheimer""s disease, and neurodegeneracies of the basal ganglia. The rate of occurrence of neurodegenerative disorders of central nervous system increases worldwide. Stroke occupies the third highest cause of death following cardiovascular diseases and malignant tumors (see: Parnetti, L. et al., Drug, and 53:752 (1997)).
Antioxidants protecting neuron cell of brain from oxidative stress include vitamin E derivatives such as Trolox (see: J. Med. Chem., 38:453 (1995)), glutathione peroxidase (hereinafter, referred to as xe2x80x9cGPxxe2x80x9d) mimics (see: Daiichi Pharmaceutical Co., Ltd., Annual Report (1999); WO 9808831; U.S. Pat. No. 5,008,394; J. Am. Chem. Soc., 119:2079-2083 (1997); Adv. Pharmacol., 38:229 (1996)), superoxide dismutase (SOD) mimics (see: U.S. Pat. No. 5,827,880), and spin trapping agents (see: J. Med. Chem., 39:4988 (1996); U.S. Pat. No. 5,475,032).
A GPx mimic is a synthesized compound mimicking the function of the selenocystein from GPx active site. A well-known GPx mimic, Ebselen seems to have no major toxicity in preclinical and clinical tests and it is proposed as a potential drug for stroke. Ebselen is, however, very little soluble in water, even in the presence of an excess of glutathione (GSH), which limits its pharmacological applications.
Spin trapping agents may be developed as an antioxidant if they can trap hazardous free radicals enough, which include xcex1-phenyl-N-tert-butylnitrone (PBN), and various derivatives of PBN have been developed. Generally, nitrone moiety increases the solubility of compounds in water. However, it has revealed shortcomings such as a low lipid peroxidation inhibition activity in vitro and a low protection of brain cells in vivo (see: Fevig, Thomas L. et al., J. Med. Chem., 39:4988-4996 (1996)).
The present inventors synthesized novel compounds by introducing spin trapping agent, i.e., nitrone moiety into GPx mimic, Ebselen, which have not only increased solubility in water and low toxicity but also peroxidase function and radical trapping function. Also, they found that the said compounds have effective antioxidant activity for the treatment and prevention of cell death of brain cells while showing low toxicity. As a result, the said compounds could be potential drug candidates for the treatment and prevention of cell death of brain cells.
The first object of the present invention is, therefore, to provide new type of antioxidants which are GPx mimics containing spin trapping moiety.
The second object of the invention is to provide a process for preparing the said antioxidants.
The third object of the invention is to provide pharmaceutical compositions comprising the said antioxidants as an active ingredient for the treatment and prevention of medical dysfunctions and diseases such as stroke, Parkinson""s disease, and Alzheimer""s disease caused by reactive oxygen species.
The fourth object of the invention is to provide a method for treating a living body afflicted with a condition requiring an antioxidant agent, in particular acute and progressive neurodegenerative disorders, by way of administering to the living body the said pharmaceutical preparations.